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Importance: The optimal approach for treatment deescalation in human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas (OPSCCs) is unknown., Objective: To assess a primary radiotherapy (RT) approach vs a primary transoral surgical (TOS) approach in treatment deescalation for HPV-related OPSCC., Design, Setting, and Participants: This international, multicenter, open-label parallel-group phase 2 randomized clinical trial was conducted at 9 tertiary academic cancer centers in Canada and Australia and enrolled patients with T1-T2N0-2 p16-positive OPSCC between February 13, 2018, and November 17, 2020. Patients had up to 3 years of follow-up., Interventions: Primary RT (consisting of 60 Gy of RT with concurrent weekly cisplatin in node-positive patients) vs TOS and neck dissection (ND) (with adjuvant reduced-dose RT depending on pathologic findings)., Main Outcomes and Measures: The primary end point was overall survival (OS) compared with a historical control. Secondary end points included progression-free survival (PFS), quality of life, and toxic effects., Results: Overall, 61 patients were randomized (30 [49.2%] in the RT arm and 31 [50.8%] in the TOS and ND arm; median [IQR] age, 61.9 [57.2-67.9] years; 8 women [13.6%] and 51 men [86.4%]; 31 [50.8%] never smoked). The trial began in February 2018, and accrual was halted in November 2020 because of excessive toxic effects in the TOS and ND arm. Median follow-up was 17 months (IQR, 15-20 months). For the OS end point, there were 3 death events, all in the TOS and ND arm, including the 2 treatment-related deaths (0.7 and 4.3 months after randomization, respectively) and 1 of myocardial infarction at 8.5 months. There were 4 events for the PFS end point, also all in the TOS and ND arm, which included the 3 mortality events and 1 local recurrence. Thus, the OS and PFS data remained immature. Grade 2 to 5 toxic effects occurred in 20 patients (67%) in the RT arm and 22 (71%) in the TOS and ND arm. Mean (SD) MD Anderson Dysphagia Inventory scores at 1 year were similar between arms (85.7 [15.6] and 84.7 [14.5], respectively)., Conclusions and Relevance: In this randomized clinical trial, TOS was associated with an unacceptable risk of grade 5 toxic effects, but patients in both trial arms achieved good swallowing outcomes at 1 year. Long-term follow-up is required to assess OS and PFS outcomes., Trial Registration: Clinicaltrials.gov Identifier: NCT03210103.

Importance: Although the survival impact of human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OPSCC) is well known, there has been conflicting and scarce evidence on the role of HPV in non-OPSCC., Objective: To undertake a Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)-compliant systematic review and meta-analysis of all published studies on the association between HPV status and survival outcomes in patients with non-OPSCC, analyzing each site separately., Data Sources: PubMed, CINAHL, and Embase were searched from 1946 to December 16, 2019, for English-language articles., Study Selection: Analysis comprised randomized clinical trials or observational studies that each included at least 10 patients with non-OPSCC in which the presence of HPV was analyzed, survival outcomes were reported, and a clinical follow-up of 1 year or more was performed. Studies excluded were those in which data on OPSCC and non-OPSCC were not distinguished between both cohorts and studies on patients with distant metastatic tumors at diagnosis. Final analysis included outcomes that were analyzed in at least 3 studies., Data Extraction and Synthesis: Two reviewers independently abstracted the data. Risk of bias was estimated with the Newcastle-Ottawa Scale. Meta-analysis was performed using the random-effects model., Main Outcomes and Measures: The primary end point was overall survival (OS); secondary end points were disease-specific survival (DSS) and disease-free survival (DFS)., Results: Of the 3947 articles screened, a total of 22 observational and 2 randomized clinical trials were included in the analysis, representing 24 854 patients. In oral cavity locations, OS was not significantly associated with HPV positivity (hazard ratio [HR], 1.16; 95% CI, 0.83-1.61; I2 = 71%); however, HPV-positive tumors showed worse DFS (HR, 1.81; 95% CI, 1.12-2.91; I2 = 47%). Laryngeal and hypopharyngeal HPV-positive tumors were associated with improved OS (HR, 0.71; 95% CI, 0.54-0.92; I2 = 38% and HR, 0.60; 95% CI, 0.47-0.76; I2 = 0%), respectively, whereas, in nasopharyngeal locations HPV was not associated with OS (HR, 0.82; 95% CI, 0.49-1.38; I2 = 46%) or DSS (HR, 0.55; 95% CI, 0.22-1.42; I2 = 65%)., Conclusions and Relevance: In this meta-analysis of 24 studies, HPV was associated with improved OS in laryngeal and hypopharyngeal locations but not in the oral cavity and the nasopharynx. This information may be useful for future clinical studies of laryngeal and hypopharyngeal tumors and whether HPV status should be incorporated in prognostication of patients with these cancers.

Importance: There is a need to summarize the available evidence and provide quantitative data of the most important prognostic factors for patients with metastatic cutaneous squamous cell carcinoma of the head and neck region with regional lymph node metastasis (McSCCHN)., Objective: To undertake a PRISMA-compliant systematic review and meta-analysis of all published studies on the risk factors for overall survival (OS), locoregional control (LRC), locoregional recurrence (LRR), and disease-specific survival (DSS) for patients with McSCCHN., Data Sources: PubMed, CINAHL, and Embase were searched from 1946 to August 2018 for English-language articles., Study Selection: Inclusion criteria were randomized clinical trials or observational studies reporting on at least 10 patients with McSCCHN; studies analyzing 1 defined risk factor; reporting OS, LRC, LRR, or DSS; and clinical follow-up of 1 year of more. For the final analysis we included risk factors that were analyzed for the same outcome in at least 3 studies. Of the 2923 articles screened, 21 articles met the inclusion criteria., Data Extraction and Synthesis: PRISMA guidelines were used for abstracting the data. Two reviewers independently abstracted the data. Risk of bias was estimated with the Newcastle-Ottawa Scale. Meta-analysis was performed using the random-effects model. All analysis took place between January and October 2018., Main Outcomes and Measures: The primary end point was OS. Secondary end points included LRC, LRR, and DSS., Results: A total of 20 observational studies and 1 randomized clinical trial were identified, representing 3534 patients (some reviewed articles reported no demographic characteristics), and were included in the analysis. Significant risk factors associated with OS were immunosuppression (hazard ratio [HR] of death, 2.66; 95% CI, 2.26-3.13), extracapsular spread (HR, 1.90; 95% CI, 1.12-3.23), adjuvant radiotherapy (HR, 0.45; 95% CI, 0.27-0.78), lymph node ratio (HR, 1.91; 95% CI, 1.09-3.35), and advanced age (HR, 1.03; 95% CI, 1.00-1.07). Immunosuppression (HR, 3.82; 95% CI, 2.47-5.92) and adjuvant radiotherapy (HR, 0.52; 95% CI, 0.33-0.84) were also significant risk factors for DSS., Conclusions and Relevance: Immunosuppressed patients and those with extracapsular extension have poor prognosis. Adjuvant radiotherapy is associated with an improvement in OS. These risk factors will assist with better risk stratification and may also help to inform future clinical trials.

Importance: Locoregional recurrence of oral cavity squamous cell carcinoma (OCSCC) continues to be a life-threatening and difficult clinical situation. Salvage surgery can result in significant morbidities, and survival following recurrence is poor., Objective: To outline prognostic factors influencing overall survival (OS) following salvage surgery for OCSCC to guide management of treatment for patients with locoregionally recurrent disease., Design, Setting, and Participants: The medical records of 293 patients presenting to the London Health Sciences Center with locoregionally recurrent OCSCC between October 5, 1999, and May 2, 2011, were retrospectively reviewed. The primary outcome was OS from salvage treatment to last follow-up or death. Univariate analyses were carried out using the Cox proportional hazards regression model. A recursive partitioning analysis was used to create risk groups based on prognosis. Analysis was conducted from December 8, 2015, to February 26, 2016., Results: Of the 293 patients evaluated, 59 (20%) had recurrence identified after their initial OCSCC treatment; 39 (66%) were men, and the mean (SD) age at diagnosis was 62.2 (11.8) years. Thirty-nine (66%) of these patients underwent salvage surgery for locoregional recurrence with curative intent. Five-year OS from the time of salvage surgery was 43%. Recursive partitioning analysis identified 3 risk groups: (1) high risk (patients who received adjuvant chemoradiotherapy or radiotherapy after initial surgery) with 5-year OS rate of 10% (hazard ratio [HR], 9.41; 95% CI, 2.68-33.04), (2) intermediate risk (previous surgery alone, age ≥62 years) with a 5-year OS rate of 39% (HR, 2.95; 95% CI, 0.86-10.09), and (3) low risk (previous surgery alone, age <62 years) with 5-year OS rate of 74%., Conclusions and Relevance: This recursive partitioning analysis identified 3 prognostic groups in patients undergoing salvage surgery for recurrent OCSCC. The marked differences in survival between these groups should be taken into consideration when counselling and managing treatment for patients with locoregionally recurrent disease.

Importance: Large-scale whole-exome sequencing studies of head and neck squamous cell carcinoma (HNSCC) have established that the disease is dominated by frequent mutations in tumor suppressor genes with rare activating mutations in oncogenes that would be easily targetable with molecular agents. There was evidence in these reports, however, that activating mutations in phosphoinositide 3-kinase catalytic subunit p110α (PIK3CA) were common in patients with human papillomavirus (HPV)-positive tumors. We set out to test this prediction in oropharyngeal patient samples from our institution., Objective: To confirm whether activating mutations in PIK3CA are frequent in HPV-positive HNSCC because this mutated oncogene represents a potential therapeutic target., Design, Setting, and Participants: A retrospective search of the London Health Sciences Centre pathology database was performed to identify oropharyngeal cancer samples. DNA from pretreatment primary site biopsy samples from 87 patients were tested for high-risk HPV types 16 and 18 by real-time polymerase chain reaction., Main Outcomes and Measures: Samples were tested for activating mutations at the 3 mutational hot spots (codons 542, 545, and 1047) by polymerase chain reaction followed by Sanger sequencing using forward and reverse primers., Results: Only 4 of 41 HPV-negative tumors (10%) demonstrated PIK3CA hot spot mutations, including 3 at codon 1047 and 1 at codon 542. Of 46 HPV-positive tumors, 13 (28%) demonstrated activating PIK3CA mutations, including 7 at codon 542, 5 at codon 545, and 1 at codon 1047. The difference in PIK3CA mutation frequency was significantly different between HPV-positive and HPV-negative cancers (P = .03)., Conclusions and Relevance: Although there has been a suggestion that activating PIK3CA mutations are common in HPV-positive HNSCC, to our knowledge, this is the first study to clearly identify this phenomenon. Targeting PIK3CA with molecular agents in HPV-positive patients may be a mechanism to improve cure rates and decrease treatment toxic effects in this rapidly growing cohort of patients.

Importance: Provides an approach to osseous free flap selection for reconstruction of segmental mandible defects that takes into consideration general medical status of the patient and reconstruction requirements; demonstrates the complementary qualities of fibular and subscapular system free flaps; and describes the different surgical indications for lateral border scapular and scapular tip free flaps., Objectives: To review our experience with osseous mandible reconstruction comparing the fibular and subscapular system free flaps, determine reconstruction-specific and general health variables that may differ between these patient groups, and present our approach to oromandibular reconstruction., Design: Retrospective study., Setting: Academic tertiary care medical center., Participants: A total of 110 patients (68 male, 42 female) undergoing single-stage oromandibular reconstructions with free-tissue transfers between May 1, 2006, and May 30, 2012., Intervention: Single-stage oromandibular reconstruction with free-tissue transfer., Main Outcome Measures: Differences in patient demographics, bone and soft-tissue aspects of the reconstruction, operative time, flap outcomes, and major postoperative complications between fibular, lateral scapular border, and scapular tip free flaps., Results: A total of 110 patients underwent 113 reconstructions, including 58 fibular free flaps (FFFs) (51.3%) and 55 subscapular system flaps (48.7%). Of the subscapular system free flaps, 27 flaps (49%) were scapular tip free flaps (STFFs) based on the angular artery branch of the thoracodorsal pedicle; the remaining 28 cases were lateral scapular border flaps (LSBFs). Patients undergoing reconstruction with FFFs were significantly younger than their subscapular system flap counterparts (56 vs 70 years, P < .001). Mean mandible defect lengths were similar for patients undergoing FFF and LSBF reconstruction (7.8 and 7.7 cm, respectively); STFFs were used to reconstruct significantly shorter defects (mean, 6.0 cm, P < .001). The FFFs were more commonly used for anterior mandible defects in which multiple osteotomies and limited soft tissue were required, while subscapular flaps were more commonly used for linear mandible defects with complex soft-tissue requirements. A single complete flap loss occurred in a patient who underwent reconstruction with an STFF; other complication rates were similar between groups., Conclusions and Relevance: The FFFs and subscapular flaps are complementary options for oromandibular reconstruction. The FFF is ideal for younger patients, extended defects, multiple osteotomies, and limited soft-tissue requirements. The subscapular system free flaps (LSBF and STFF) are excellent options for (1) elderly patients; (2) those with significant comorbidities, such as peripheral vascular disease; and (3) mandible defects associated with complex soft-tissue requirements. Furthermore, the STFF offers a reliable option to reconstruct short-segment defects, in particular, defects involving the angle of the mandible.

Objective: To conduct high-throughput mutational analysis in 6 commonly used head and neck cancer cell lines. Comprehensive mutation analysis of primary head and neck squamous cell carcinoma (HNSCC) tumors has recently been reported, and mutations in the NOTCH receptors, TP53 and CDKN2A, were key findings. Established cell lines are valuable tools to study cancer in vitro. Similar high-throughput mutational analysis of head and neck cancer cell lines is necessary to confirm their mutational profile., Design: DNA was extracted from American Type Culture Collection (ATCC) cell lines Cal27, Detroit562, FaDu, SCC4, SCC15, and SCC25. Cell line identity was confirmed by short tandem repeat (STR) analysis, and human papillomavirus (HPV) infection status was assessed by real-time polymerase chain reaction. A total of 535 cancer-associated genes were sequenced through a limited exome capture on the Illumina HiSeq system., Setting: London Regional Cancer Program., Results: The identity of the 6 cell lines was confirmed by STR analysis, and all lines tested negative for HPV infection. We achieved an average of 129-fold coverage with paired-end 100 base-pair reads. Sequencing revealed an average of 38 damaging mutations in each cell line (range, 30-45). The TP53 mutations, predicted to confer loss of function, were noted in all cell lines, and damaging CDKN2A mutations were found in all lines except SCC15., Conclusions: High-throughput sequencing of head and neck cancer cell lines revealed similar mutations to those observed in primary tumors. Thus, these lines reflect the tumor biology of HNSCC and can serve as valuable models to study HNSCC in vitro.

Objectives: To determine the long-term retention of a 3-dimentional (3-D) educational computer model of the larynx to teach laryngeal anatomy and to compare it with standard written instruction (SWI)., Design: Prospective randomized controlled trial., Setting: University education program., Participants: One hundred health care students., Interventions: For short-term assessment, 50 students were randomized to the 3-D model and 50 to SWI and were tested using a 20-question laryngeal test. Six months later, the same students were invited to retake the laryngeal anatomy test to examine long-term retention., Main Outcome Measure: The score on a 20-item Web-based test that assessed the students' level of knowledge of laryngeal anatomy approximately 6 months after their initial exposure to the laryngeal anatomy teaching intervention., Results: Sixty-two students retook the test: 3-D (n = 30) and SWI (n = 32). No significant difference was noted in mean scores (P = .54) and change in scores (P = .59) between short- and long-term retention on the laryngeal anatomy test. There was a trend toward an increase in 3-D scores in both groups (P = .07) and a significant increase in 3-D scores in the 3-D group only (P = .049)., Conclusions: A low-fidelity model (SWI) is just as effective as a high-fidelity model (3-D) in teaching laryngeal anatomy. The acquired knowledge from either educational intervention may last up to 6 months for long-term retention. This study is one of the few in medical education to examine long-term retention.

Objectives: To create a 3-dimensional (3D) educational computer model of the larynx, to assess the feasibility of this learning module on a Web-based platform, and to obtain student feedback on the module., Design: Male and female adult cadaveric necks were scanned with microcomputed tomographic and magnetic resonance imaging scanners. Key structures were identified on each slice of the computed tomogram and/or magnetic resonance image and analyzed with a segmentation software package. Then, the images were exported into Microsoft Powerpoint. Visual text and audio commentary were added. Real cases of a child's larynx, an adult with a tracheostomy, and a patient with laryngeal carcinoma were included. The computer module was launched on a password-protected, Web-based platform., Participants: Fifty-eight first-year medical students (38% male; mean [SD] age, 23 [1.8] years) were invited to evaluate the module and to complete a survey., Results: Most students thought that the 3D computer module was effective (60%), clear (66%), and user friendly (72%); most students (81%) thought that it was easier to understand laryngeal anatomy when they could visualize it in 3D; and most students (83%) said that they would like lectures better if they were supplemented with 3D computer modules., Conclusion: A 3D educational computer model of the larynx has been successfully created and warmly received by medical students.

Objective: To evaluate facial impairment and disability with respect to quality of life in patients with facial paresis after vestibular schwannoma surgery., Design: Cross-sectional observational study., Setting: Academic, tertiary care hospital., Patients: All consecutive patients during a 5-year period who underwent vestibular schwannoma surgery., Main Outcome Measures: The validated, patient-graded Facial Clinimetric Evaluation (FaCE) scale questionnaire was administered to all study patients. Main outcome measures included total and social function FaCE scores. Subgroup analysis was performed on patient factors (age and sex), surgical factors (tumor size and time since operation), and House-Brackmann grade., Results: A total of 56 FaCE questionnaires were returned (85% response rate): 28 patients (50%) had normal facial function (House-Brackmann grade I), and 28 patients (50%) had abnormal facial function (House-Brackmann grades II-VI). There were no demographic differences between the normal and abnormal groups. The normal group had a total FaCE score of 96.2 compared with 67.1 in the abnormal group (P<.05). Subgroup analysis of patients with facial paresis revealed that age, sex, time since operation, tumor size, and House-Brackmann grade were not statistically significant factors predicting the FaCE social function score (P<.05)., Conclusions: Facial paresis is an important complication of vestibular schwannoma surgery and will impair a patient's quality of life. The level of impairment may not be predicted by a patient's age, sex, tumor size, time since operation, or severity of facial paresis.